Everything you ever wanted to know about Ambien

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AMBIEN® Prescribing Information

zolpidem tartrate

DESCRIPTION | CLINICAL PHARMACOLOGY | INDICATIONS AND USAGE |

CONTRAINDICATIONS | WARNINGS | PRECAUTIONS | ADVERSE REACTIONS | DRUG

ABUSE AND DEPENDENCE | OVERDOSAGE | DOSAGE AND ADMINISTRATION | HOW

SUPPLIED | INFORMATION FOR PATIENTS TAKING AMBIEN | SIDE EFFECTS | SPECIAL

CONCERNS | SAFE USE OF SLEEPING MEDICINES |

DESCRIPTION

Ambien (zolpidem tartrate), is a non-benzodiazepine hypnotic of the

imidazopyridine class and is available in 5-mg and 10-mg strength tablets for

oral administration.

Chemically, zolpidem is N,N,6-trimethyl-2-p-tolyl-imidazo[1,2-

a]pyridine-3-acetamide L-(+)-tartrate (2:1). It has the following structure:

Zolpidem tartrate is a white to off-white crystalline powder that is sparingly

soluble in water, alcohol, and propylene glycol. It has a molecular weight of

764.88.

Each Ambien tablet includes the following inactive ingredients: hydroxypropyl

methylcellulose, lactose, magnesium stearate, microcrystalline cellulose,

polyethylene glycol, sodium starch glycolate, and titanium dioxide; the 5-mg

tablet also contains FD & C Red No. 40, iron oxide colorant, and polysorbate 80.

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CLINICAL PHARMACOLOGY

Pharmacodynamics: Subunit modulation of the GABAA receptor chloride channel

macromolecular complex is hypothesized to be responsible for sedative,

anticonvulsant, anxiolytic, and myorelaxant drug properties. The major

modulatory site of the GABAA receptor complex is located on its alpha () subunit

and is referred to as the benzodiazepine (BZ) or omega () receptor. At least

three subtypes of the () receptor have been identified.

While zolpidem is a hypnotic agent with a chemical structure unrelated to

benzodiazepines, barbiturates, or other drugs with known hypnotic properties, it

interacts with a GABA-BZ receptor complex and shares some of the pharmacological

properties of the benzodiazepines. In contrast to the benzodiazepines, which

nonselectively bind to and activate all omega receptor subtypes, zolpidem in

vitro binds the (1) receptor preferentially with a high affinity ratio of the

alpha1/alpha5 subunits. The (1) receptor is found primarily on the Lamina IV of

the sensorimotor cortical regions, substantia nigra (pars reticulata),

cerebellum molecular layer, olfactory bulb, ventral thalamic complex, pons,

inferior colliculus, and globus pallidus. This selective binding of zolpidem on

the (1) receptor is not absolute, but it may explain the relative absence of

myorelaxant and anticonvulsant effects in animal studies as well as the

preservation of deep sleep (stages 3 and 4) in human studies of zolpidem at

hypnotic doses.

Pharmacokinetics: The pharmacokinetic profile of Ambien is characterized by

rapid absorption from the GI tract and a short elimination half-life (T1/2) in

healthy subjects. In a single-dose crossover study in 45 healthy subjects

administered 5- and 10-mg zolpidem tartrate tablets, the mean peak

concentrations (Cmax) were 59 (range: 29 to 113) and 121 (range: 58 to 272)

ng/mL, respectively, occurring at a mean time (Tmax) of 1.6 hours for both. The

mean Ambien elimination half-life was 2.6 (range: 1.4 to 4.5) and 2.5 (range:

1.4 to 3.8) hours, for the 5- and 10-mg tablets, respectively. Ambien is

converted to inactive metabolites that are eliminated primarily by renal

excretion. Ambien demonstrated linear kinetics in the dose range of 5 to 20 mg.

Total protein binding was found to be 92.5±0.1% and remained constant,

independent of concentration between 40 and 790 ng/mL. Zolpidem did not

accumulate in young adults following nightly dosing with 20-mg zolpidem tartrate

tablets for 2 weeks.

A food-effect study in 30 healthy male volunteers compared the pharmacokinetics

of Ambien 10 mg when administered while fasting or 20 minutes after a meal.

Results demonstrated that with food, mean AUC and Cmax were decreased by 15% and

25%, respectively, while mean Tmax was prolonged by 60% (from 1.4 to 2.2 hr).

The half-life remained unchanged. These results suggest that, for faster sleep

onset, Ambien should not be administered with or immediately after a meal.

In the elderly, the dose for Ambien should be 5 mg (see Precautions and Dosage

and Administration). This recommendation is based on several studies in which

the mean Cmax, T1/2, and AUC were significantly increased when compared to

results in young adults. In one study of eight elderly subjects (>70 years), the

means for Cmax, T1/2, and AUC significantly increased by 50% (255 vs 384 ng/mL),

32% (2.2 vs 2.9 hr), and 64% (955 vs 1,562 ng·hr/mL), respectively, as compared

to younger adults (20 to 40 years) following a single 20-mg oral zolpidem dose.

Ambien did not accumulate in elderly subjects following nightly oral dosing of

10 mg for 1 week.

The pharmacokinetics of Ambien in eight patients with chronic hepatic

insufficiency were compared to results in healthy subjects. Following a single

20-mg oral zolpidem dose, mean Cmax and AUC were found to be two times (250 vs

499 ng/mL) and five times (788 vs 4,203 ng·hr/mL) higher, respectively, in

hepatically compromised patients. Tmax did not change. The mean half-life in

cirrhotic patients of 9.9 hr (range: 4.1 to 25.8 hr) was greater than that

observed in normals of 2.2 hr (range: 1.6 to 2.4 hr). Dosing should be modified

accordingly in patients with hepatic insufficiency (see Precautions and Dosage

and Administration).

The pharmacokinetics of zolpidem tartrate were studied in 11 patients with

end-stage renal failure (mean ClCr=6.5±1.5 mL/min) undergoing hemodialysis three

times a week, who were dosed with zolpidem 10 mg orally each day for 14 or 21

days. No statistically significant differences were observed for Cmax, Tmax,

half-life, and AUC between the first and last day of drug administration when

baseline concentration adjustments were made. On day 1, Cmax was 172±29 ng/mL

(range: 46 to 344 ng/mL). After repeated dosing for 14 or 21 days, Cmax was

203±32 ng/mL (range: 28 to 316 ng/mL). On day 1, Tmax was 1.7±0.3 hr (range: 0.5

to 3.0 hr); after repeated dosing Tmax was 0.8±0.2 hr (range: 0.5 to 2.0 hr).

This variation is accounted for by noting that last-day serum sampling began 10

hours after the previous dose, rather than after 24 hours. This resulted in

residual drug concentration and a shorter period to reach maximal serum

concentration. On day 1, T1/2 was 2.4±0.4 hr (range: 0.4 to 5.1 hr). After

repeated dosing, T1/2 was 2.5±0.4 hr (range: 0.7 to 4.2 hr). AUC was 796±159

ng·hr/mL after the first dose and 818±170 ng·hr/mL after repeated dosing.

Zolpidem was not hemodialyzable. No accumulation of unchanged drug appeared

after 14 or 21 days. Ambien (zolpidem tartrate) pharmacokinetics were not

significantly different in renally impaired patients. No dosage adjustment is

necessary in patients with compromised renal function. As a general precaution,

these patients should be closely monitored.

Postulated relationship between elimination rate of hypnotics and their profile

of common untoward effects: The type and duration of hypnotic effects and the

profile of unwanted effects during administration of hypnotic drugs may be

influenced by the biologic half-life of administered drug and any active

metabolites formed. When half-lives are long, drug or metabolites may accumulate

during periods of nightly administration and be associated with impairment of

cognitive and/or motor performance during waking hours; the possibility of

interaction with other psychoactive drugs or alcohol will be enhanced. In

contrast, if half-lives, including half-lives of active metabolites, are short,

drug and metabolites will be cleared before the next dose is ingested, and

carryover effects related to excessive sedation or CNS depression should be

minimal or absent. Ambien has a short half-life and no active metabolites.

During nightly use for an extended period, pharmacodynamic tolerance or

adaptation to some effects of hypnotics may develop. If the drug has a short

elimination half-life, it is possible that a relative deficiency of the drug or

its active metabolites (ie, in relationship to the receptor site) may occur at

some point in the interval between each night's use. This sequence of events may

account for two clinical findings reported to occur after several weeks of

nightly use of other rapidly eliminated hypnotics, namely, increased wakefulness

during the last third of the night, and the appearance of increased signs of

daytime anxiety. Increased wakefulness during the last third of the night as

measured by polysomnography has not been observed in clinical trials with

Ambien.

Controlled trials supporting safety and efficacy

Transient insomnia: Normal adults experiencing transient insomnia (n=462) during

the first night in a sleep laboratory were evaluated in a double-blind, parallel

group, single-night trial comparing two doses of zolpidem (7.5 and 10 mg) and

placebo. Both zolpidem doses were superior to placebo on objective

(polysomnographic) measures of sleep latency, sleep duration, and number of

awakenings.

Normal elderly adults (mean age 68) experiencing transient insomnia (n=35)

during the first two nights in a sleep laboratory were evaluated in a

double-blind, crossover, 2-night trial comparing four doses of zolpidem (5, 10,

15 and 20 mg) and placebo. All zolpidem doses were superior to placebo on the

two primary PSG parameters (sleep latency and efficiency) and all four

subjective outcome measures (sleep duration, sleep latency, number of

awakenings, and sleep quality).

Chronic insomnia: Zolpidem was evaluated in two controlled studies for the

treatment of patients with chronic insomnia (most closely resembling primary

insomnia, as defined in the APA Diagnostic and Statistical Manual of Mental

Disorders, DSM-IVT). Adult outpatients with chronic insomnia (n=75) were

evaluated in a double-blind, parallel group, 5-week trial comparing two doses of

zolpidem tartrate (10 and 15 mg) and placebo. On objective (polysomnographic)

measures of sleep latency and sleep efficiency, zolpidem 15 mg was superior to

placebo for all 5 weeks; zolpidem 10 mg was superior to placebo on sleep latency

for the first 4 weeks and on sleep efficiency for weeks 2 and 4. Zolpidem was

comparable to placebo on number of awakenings at both doses studied.

Adult outpatients (n=141) with chronic insomnia were also evaluated in a

double-blind, parallel group, 4-week trial comparing two doses of zolpidem (10

and 15 mg) and placebo. Zolpidem 10 mg was superior to placebo on a subjective

measure of sleep latency for all 4 weeks, and on subjective measures of total

sleep time, number of awakenings, and sleep quality for the first treatment

week. Zolpidem 15 mg was superior to placebo on a subjective measure of sleep

latency for the first 3 weeks, on a subjective measure of total sleep time for

the first week, and on number of awakenings and sleep quality for the first 2

weeks.

Next-day residual effects: Next-day residual effects of Ambien were evaluated in

seven studies involving normal volunteers. In three studies in adults (including

one study in a phase advance model of transient insomnia) and in one study in

elderly subjects, a small but statistically significant decrease in performance

was observed in the Digit Symbol Substitution Test (DSST) when compared to

placebo. Studies of Ambien in non-elderly patients with insomnia did not detect

evidence of next-day residual effects using the DSST, the Multiple Sleep Latency

Test (MSLT), and patient ratings of alertness.

Rebound effects: There was no objective (polysomnographic) evidence of rebound

insomnia at recommended doses seen in studies evaluating sleep on the nights

following discontinuation of Ambien (zolpidem tartrate). There was subjective

evidence of impaired sleep in the elderly on the first post-treatment night at

doses above the recommended elderly dose of 5 mg.

Memory impairment: Controlled studies in adults utilizing objective measures of

memory yielded no consistent evidence of next-day memory impairment following

the administration of Ambien. However, in one study involving zolpidem doses of

10 and 20 mg, there was a significant decrease in next-morning recall of

information presented to subjects during peak drug effect (90 minutes

post-dose), ie, these subjects experienced anterograde amnesia. There was also

subjective evidence from adverse event data for anterograde amnesia occurring in

association with the administration of Ambien, predominantly at doses above 10

mg.

Effects on sleep stages: In studies that measured the percentage of sleep time

spent in each sleep stage, Ambien has generally been shown to preserve sleep

stages. Sleep time spent in stages 3 and 4 (deep sleep) was found comparable to

placebo with only inconsistent, minor changes in REM (paradoxical) sleep at the

recommended dose.

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INDICATIONS AND USAGE

Ambien (zolpidem tartrate) is indicated for the short-term treatment of

insomnia. Ambien has been shown to decrease sleep latency and increase the

duration of sleep for up to 35 days in controlled clinical studies (see Clinical

Pharmacology: Controlled trials supporting safety and efficacy).

Hypnotics should generally be limited to 7 to 10 days of use, and reevaluation

of the patient is recommended if they are to be taken for more than 2 to 3

weeks. Ambien should not be prescribed in quantities exceeding a 1-month supply

(see Warnings).

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CONTRAINDICATIONS

None known.

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WARNINGS

Since sleep disturbances may be the presenting manifestation of a physical

and/or psychiatric disorder, symptomatic treatment of insomnia should be

initiated only after a careful evaluation of the patient. The failure of

insomnia to remit after 7 to 10 days of treatment may indicate the presence of a

primary psychiatric and/or medical illness which should be evaluated. Worsening

of insomnia or the emergence of new thinking or behavior abnormalities may be

the consequence of an unrecognized psychiatric or physical disorder. Such

findings have emerged during the course of treatment with sedative/hypnotic

drugs, including Ambien. Because some of the important adverse effects of Ambien

appear to be dose related (see Precautions and Dosage and Administration), it is

important to use the smallest possible effective dose, especially in the

elderly.

A variety of abnormal thinking and behavior changes have been reported to occur

in association with the use of sedative/ hypnotics. Some of these changes may be

characterized by decreased inhibition (eg, aggressiveness and extroversion that

seemed out of character), similar to effects produced by alcohol and other CNS

depressants. Other reported behavioral changes have included bizarre behavior,

agitation, hallucinations, and depersonalization. Amnesia and other

neuropsychiatric symptoms may occur unpredictably. In primarily depressed

patients, worsening of depression, including suicidal thinking, has been

reported in association with the use of sedative/hypnotics.

It can rarely be determined with certainty whether a particular instance of the

abnormal behaviors listed above is drug induced, spontaneous in origin, or a

result of an underlying psychiatric or physical disorder. Nonetheless, the

emergence of any new behavioral sign or symptom of concern requires careful and

immediate evaluation.

Following the rapid dose decrease or abrupt discontinuation of

sedative/hypnotics, there have been reports of signs and symptoms similar to

those associated with withdrawal from other CNS-depressant drugs (see Drug Abuse

and Dependence).

Ambien, like other sedative/hypnotic drugs, has CNS-depressant effects. Due to

the rapid onset of action, Ambien should only be ingested immediately prior to

going to bed. Patients should be cautioned against engaging in hazardous

occupations requiring complete mental alertness or motor coordination such as

operating machinery or driving a motor vehicle after ingesting the drug,

including potential impairment of the performance of such activities that may

occur the day following ingestion of Ambien. Ambien showed additive effects when

combined with alcohol and should not be taken with alcohol. Patients should also

be cautioned about possible combined effects with other CNS-depressant drugs.

Dosage adjustments may be necessary when Ambien is administered with such agents

because of the potentially additive effects.

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PRECAUTIONS

General

Use in the elderly and/or debilitated patients: Impaired motor and/or cognitive

performance after repeated exposure or unusual sensitivity to sedative/hypnotic

drugs is a concern in the treatment of elderly and/or debilitated patients.

Therefore, the recommended Ambien dosage is 5 mg in such patients (see Dosage

and Administration) to decrease the possibility of side effects. These patients

should be closely monitored.

Use in patients with concomitant illness: Clinical experience with Ambien

(zolpidem tartrate) in patients with concomitant systemic illness is limited.

Caution is advisable in using Ambien in patients with diseases or conditions

that could affect metabolism or hemodynamic responses. Although studies did not

reveal respiratory depressant effects at hypnotic doses of Ambien in normals or

in patients with mild to moderate chronic obstructive pulmonary disease (COPD),

a reduction in the Total Arousal Index together with a reduction in lowest

oxygen saturation and increase in the times of oxygen desaturation below 80% and

90% was observed in patients with mild-to-moderate sleep apnea when treated with

Ambien (10 mg) when compared to placebo. However, precautions should be observed

if Ambien is prescribed to patients with compromised respiratory function, since

sedative/hypnotics have the capacity to depress respiratory drive.

Post-marketing reports of respiratory insufficiency, most of which involved

patients with pre-existing respiratory impairment, have been received. Data in

end-stage renal failure patients repeatedly treated with Ambien did not

demonstrate drug accumulation or alterations in pharmacokinetic parameters. No

dosage adjustment in renally impaired patients is required; however, these

patients should be closely monitored (see Pharmacokinetics). A study in subjects

with hepatic impairment did reveal prolonged elimination in this group;

therefore, treatment should be initiated with 5 mg in patients with hepatic

compromise, and they should be closely monitored.

Use in depression: As with other sedative/hypnotic drugs, Ambien should be

administered with caution to patients exhibiting signs or symptoms of

depression. Suicidal tendencies may be present in such patients and protective

measures may be required. Intentional overdosage is more common in this group of

patients; therefore, the least amount of drug that is feasible should be

prescribed for the patient at any one time.

Information for patients: Patient information is printed at the end of this

insert. To assure safe and effective use of Ambien, this information and

instructions provided in the patient information section should be discussed

with patients.

Laboratory tests: There are no specific laboratory tests recommended.

Drug interactions

CNS-active drugs: Ambien was evaluated in healthy volunteers in single-dose

interaction studies for several CNS drugs. A study involving haloperidol and

zolpidem revealed no effect of haloperidol on the pharmacokinetics or

pharmacodynamics of zolpidem. Imipramine in combination with zolpidem produced

no pharmacokinetic interaction other than a 20% decrease in peak levels of

imipramine, but there was an additive effect of decreased alertness. Similarly,

chlorpromazine in combination with zolpidem produced no pharmacokinetic

interaction, but there was an additive effect of decreased alertness and

psychomotor performance. The lack of a drug interaction following single-dose

administration does not predict a lack following chronic administration.

An additive effect on psychomotor performance between alcohol and zolpidem was

demonstrated.

A single-dose interaction study with zolpidem 10 mg and fluoxetine 20 mg at

steady-state levels in male volunteers did not demonstrate any clinically

significant pharmacokinetic or pharmacodynamic interactions. When multiple doses

of zolpidem and fluoxetine at steady-state concentrations were evaluated in

healthy females, the only significant change was a 17% increase in the zolpidem

half-life. There was no evidence of an additive effect in psychomotor

performance.

Following five consecutive nightly doses of zolpidem 10 mg in the presence of

sertraline 50 mg (17 consecutive daily doses, at 7:00 am, in healthy female

volunteers), zolpidem Cmax was significantly higher (43%) and Tmax was

significantly decreased (53%). Pharmacokinetics of sertraline and

N-desmethylsertraline were unaffected by zolpidem.

Since the systematic evaluations of Ambien (zolpidem tartrate) in combination

with other CNS-active drugs have been limited, careful consideration should be

given to the pharmacology of any CNS-active drug to be used with zolpidem. Any

drug with CNS-depressant effects could potentially enhance the CNS-depressant

effects of zolpidem.

Drugs that affect drug metabolism via cytochrome P450: A randomized,

double-blind, crossover interaction study in ten healthy volunteers between

itraconazole (200 mg once daily for 4 days) and a single dose of zolpidem (10

mg) given 5 hours after the last dose of itraconazole resulted in a 34% increase

in AUC0-> of zolpidem. There were no significant pharmacodynamic effects of

zolpidem on subjective drowsiness, postural sway, or psychomotor performance.

A randomized, placebo-controlled, crossover interaction study in eight healthy

female volunteers between 5 consecutive daily doses of rifampin (600 mg) and a

single dose of zolpidem (20 mg) given 17 hours after the last dose of rifampin

showed significant reductions of the AUC (-73%), Cmax (-58%), and T1/2 (-36%) of

zolpidem together with significant reductions in the pharmacodynamic effects of

zolpidem.

Other drugs: A study involving cimetidine/zolpidem and ranitidine/zolpidem

combinations revealed no effect of either drug on the pharmacokinetics or

pharmacodynamics of zolpidem. Zolpidem had no effect on digoxin kinetics and did

not affect prothrombin time when given with warfarin in normal subjects.

Zolpidem's sedative/hypnotic effect was reversed by flumazenil; however, no

significant alterations in zolpidem pharmacokinetics were found.

Drug/Laboratory test interactions: Zolpidem is not known to interfere with

commonly employed clinical laboratory tests. In addition, clinical data indicate

that zolpidem does not cross-react with benzodiazepines, opiates, barbiturates,

cocaine, cannabinoids, or amphetamines in two standard urine drug screens.

Carcinogenesis, mutagenesis, impairment of fertility

Carcinogenesis: Zolpidem was administered to rats and mice for 2 years at

dietary dosages of 4, 18, and 80 mg/kg/day. In mice, these doses are 26 to 520

times or 2 to 35 times the maximum 10-mg human dose on a mg/kg or mg/m2 basis,

respectively. In rats these doses are 43 to 876 times or 6 to 115 times the

maximum 10-mg human dose on a mg/kg or mg/m2 basis, respectively. No evidence of

carcinogenic potential was observed in mice. Renal liposarcomas were seen in

4/100 rats (3 males, 1 female) receiving 80 mg/kg/day and a renal lipoma was

observed in one male rat at the 18 mg/kg/day dose. Incidence rates of lipoma and

liposarcoma for zolpidem were comparable to those seen in historical controls

and the tumor findings are thought to be a spontaneous occurrence.

Mutagenesis: Zolpidem did not have mutagenic activity in several tests including

the Ames test, genotoxicity in mouse lymphoma cells in vitro, chromosomal

aberrations in cultured human lymphocytes, unscheduled DNA synthesis in rat

hepatocytes in vitro, and the micronucleus test in mice.

Impairment of fertility: In a rat reproduction study, the high dose (100 mg

base/kg) of zolpidem resulted in irregular estrus cycles and prolonged precoital

intervals, but there was no effect on male or female fertility after daily oral

doses of 4 to 100 mg base/kg or 5 to 130 times the recommended human dose in

mg/m2. No effects on any other fertility parameters were noted.

Pregnancy

Teratogenic effects: Pregnancy Category B. Studies to assess the effects of

zolpidem on human reproduction and development have not been conducted.

Teratology studies were conducted in rats and rabbits.

In rats, adverse maternal and fetal effects occurred at 20 and 100 mg base/kg

and included dose-related maternal lethargy and ataxia and a dose-related trend

to incomplete ossification of fetal skull bones. Underossification of various

fetal bones indicates a delay in maturation and is often seen in rats treated

with sedative/hypnotic drugs. There were no teratogenic effects after zolpidem

administration. The no-effect dose for maternal or fetal toxicity was 4 mg

base/kg or 5 times the maximum human dose on a mg/m2 basis.

In rabbits, dose-related maternal sedation and decreased weight gain occurred at

all doses tested. At the high dose, 16 mg base/kg, there was an increase in

postimplantation fetal loss and underossification of sternebrae in viable

fetuses. These fetal findings in rabbits are often secondary to reductions in

maternal weight gain. There were no frank teratogenic effects. The no-effect

dose for fetal toxicity was 4 mg base/kg or 7 times the maximum human dose on a

mg/m2 basis.

Because animal reproduction studies are not always predictive of human response,

this drug should be used during pregnancy only if clearly needed.

Nonteratogenic effects: Studies to assess the effects on children whose mothers

took zolpidem during pregnancy have not been conducted. However, children born

of mothers taking sedative/hypnotic drugs may be at some risk for withdrawal

symptoms from the drug during the postnatal period. In addition, neonatal

flaccidity has been reported in infants born of mothers who received

sedative/hypnotic drugs during pregnancy.

Labor and delivery: Ambien (zolpidem tartrate) has no established use in labor

and delivery.

Nursing mothers: Studies in lactating mothers indicate that the half-life of

zolpidem is similar to that in young normal volunteers (2.6±0.3 hr). Between

0.004 and 0.019% of the total administered dose is excreted into milk, but the

effect of zolpidem on the infant is unknown.

In addition, in a rat study, zolpidem inhibited the secretion of milk. The

no-effect dose was 4 mg base/kg or 6 times the recommended human dose in mg/m2.

The use of Ambien in nursing mothers is not recommended.

Pediatric use: Safety and effectiveness in pediatric patients below the age of

18 have not been established.

Geriatric use: A total of 154 patients in U.S. controlled clinical trials and

897 patients in non-U.S. clinical trials who received zolpidem were 60 years of

age. For a pool of U.S. patients receiving zolpidem at doses of 10 mg or

placebo, there were three adverse events occurring at an incidence of at least

3% for zolpidem and for which the zolpidem incidence was at least twice the

placebo incidence (ie, they could be considered drug related).

Adverse Event Zolpidem Placebo

--------------------------------------------------------------------------

Dizziness 3% 0%

Drowsiness 5% 2%

Diarrhea 3% 1%

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A total of 30/1,959 (1.5%) non-U.S. patients receiving zolpidem reported falls,

including 28/30 (93%) who were 70 years of age. Of these 28 patients, 23 (82%)

were receiving zolpidem doses >10 mg. A total of 24/1,959 (1.2%) non-U.S.

patients receiving zolpidem reported confusion, including 18/24 (75%) who were

70 years of age. Of these 18 patients, 14 (78%) were receiving zolpidem doses

>10 mg.

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ADVERSE REACTIONS

Associated with discontinuation of treatment: Approximately 4% of 1,701 patients

who received zolpidem at all doses (1.25 to 90 mg) in U.S. premarketing clinical

trials discontinued treatment because of an adverse clinical event. Events most

commonly associated with discontinuation from U.S. trials were daytime

drowsiness (0.5%), dizziness (0.4%), headache (0.5%), nausea (0.6%), and

vomiting (0.5%).

Approximately 4% of 1,959 patients who received zolpidem at all doses (1 to 50

mg) in similar foreign trials discontinued treatment because of an adverse

event. Events most commonly associated with discontinuation from these trials

were daytime drowsiness (1.1%), dizziness/vertigo (0.8%), amnesia (0.5%), nausea

(0.5%), headache (0.4%), and falls (0.4%).

Data from a clinical study in which selective serotonin reuptake inhibitor-

(SSRI) treated patients were given zolpidem revealed that four of the seven

discontinuations during double-blind treatment with zolpidem (n=95) were

associated with impaired concentration, continuing or aggravated depression, and

manic reaction; one patient treated with placebo (n=97) was discontinued after

an attempted suicide.

Incidence in controlled clinical trials

Most commonly observed adverse events in controlled trials: During short-term

treatment (up to 10 nights) with Ambien at doses up to 10 mg, the most commonly

observed adverse events associated with the use of zolpidem and seen at

statistically significant differences from placebo-treated patients were

drowsiness (reported by 2% of zolpidem patients), dizziness (1%), and diarrhea

(1%). During longer-term treatment (28 to 35 nights) with zolpidem at doses up

to 10 mg, the most commonly observed adverse events associated with the use of

zolpidem and seen at statistically significant differences from placebo-treated

patients were dizziness (5%) and drugged feelings (3%).

Adverse events observed at an incidence of 1% in controlled trials: The

following tables enumerate treatment-emergent adverse event frequencies that

were observed at an incidence equal to 1% or greater among patients with

insomnia who received Ambien in U.S. placebo-controlled trials. Events reported

by investigators were classified utilizing a modified World Health Organization

(WHO) dictionary of preferred terms for the purpose of establishing event

frequencies. The prescriber should be aware that these figures cannot be used to

predict the incidence of side effects in the course of usual medical practice,

in which patient characteristics and other factors differ from those that

prevailed in these clinical trials. Similarly, the cited frequencies cannot be

compared with figures obtained from other clinical investigators involving

related drug products and uses, since each group of drug trials is conducted

under a different set of conditions. However, the cited figures provide the

physician with a basis for estimating the relative contribution of drug and

nondrug factors to the incidence of side effects in the population studied.

The following table was derived from a pool of 11 placebo-controlled short-term

U.S. efficacy trials involving zolpidem in doses ranging from 1.25 to 20 mg. The

table is limited to data from doses up to and including 10 mg, the highest dose

recommended for use.

Incidence of Treatment-Emergent Adverse Experiences in Short-term

Placebo-Controlled Clinical Trials

(Percentage of patients reporting)

Body System/

Adverse Event* Zolpidem

(10 mg)

(N=685) Placebo

(N=473)

--------------------------------------------------------------------------

Central and Peripheral Nervous System

Headache 7 6

Drowsiness 2 -

Dizziness 1 -

Gastrointestinal System

Nausea 2 3

Diarrhea 1 -

Musculoskeletal System

Myalgia 1 2

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*Events reported by at least 1% of Ambien patients are included.

The following table was derived from a pool of three placebo-controlled

long-term efficacy trials involving Ambien (zolpidem tartrate). These trials

involved patients with chronic insomnia who were treated for 28 to 35 nights

with zolpidem at doses of 5, 10, or 15 mg. The table is limited to data from

doses up to and including 10 mg, the highest dose recommended for use. The table

includes only adverse events occurring at an incidence of at least 1% for

zolpidem patients.

Incidence of Treatment-Emergent Adverse Experiences in Long-term

Placebo-Controlled Clinical Trials

(Percentage of patients reporting)

Body System/

Adverse Event* Zolpidem

(10 mg)

(N=152) Placebo

(N=161)

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Autonomic Nervous System

Dry mouth 3 1

Body as a Whole

Allergy 4 1

Back pain 3 2

Influenza-like symptoms 2 -

Chest pain 1 -

Fatigue 1 2

Cardiovascular System

Palpitation 2 -

Central and Peripheral Nervous System

Headache 19 22

Drowsiness 8 5

Dizziness 5 1

Lethargy 3 1

Drugged feeling 3 -

Lightheadedness 2 1

Depression 2 1

Abnormal dreams 1 -

Amnesia 1 -

Anxiety 1 1

Nervousness 1 3

Sleep disorder 1 -

Gastrointestinal System

Nausea 6 6

Dyspepsia 5 6

Diarrhea 3 2

Abdominal pain 2 2

Constipation 2 1

Anorexia 1 1

Vomiting 1 1

Immunologic System

Infection 1 1

Musculoskeletal System

Myalgia 7 7

Arthralgia 4 4

Respiratory System

Upper respiratory infection 5 6

Sinusitis 4 2

Pharyngitis 3 1

Rhinitis 1 3

Skin and Appendages

Rash 2 1

Urogenital System

Urinary tract infection 2 2

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*Events reported by at least 1% of patients treated with Ambien.

Dose relationship for adverse events: There is evidence from dose comparison

trials suggesting a dose relationship for many of the adverse events associated

with zolpidem use, particularly for certain CNS and gastrointestinal adverse

events.

Adverse event incidence across the entire preapproval database: Ambien (zolpidem

tartrate) was administered to 3,660 subjects in clinical trials throughout the

U.S., Canada, and Europe. Treatment-emergent adverse events associated with

clinical trial participation were recorded by clinical investigators using

terminology of their own choosing. To provide a meaningful estimate of the

proportion of individuals experiencing treatment-emergent adverse events,

similar types of untoward events were grouped into a smaller number of

standardized event categories and classified utilizing a modified World Health

Organization (WHO) dictionary of preferred terms. The frequencies presented,

therefore, represent the proportions of the 3,660 individuals exposed to

zolpidem, at all doses, who experienced an event of the type cited on at least

one occasion while receiving zolpidem. All reported treatment-emergent adverse

events are included, except those already listed in the table above of adverse

events in placebo-controlled studies, those coding terms that are so general as

to be uninformative, and those events where a drug cause was remote. It is

important to emphasize that, although the events reported did occur during

treatment with Ambien, they were not necessarily caused by it.

Adverse events are further classified within body system categories and

enumerated in order of decreasing frequency using the following definitions:

frequent adverse events are defined as those occurring in greater than 1/100

subjects; infrequent adverse events are those occurring in 1/100 to 1/1,000

patients; rare events are those occurring in less than 1/1,000 patients.

Autonomic nervous system: Infrequent: increased sweating, pallor, postural

hypotension, syncope. Rare: abnormal accommodation, altered saliva, flushing,

glaucoma, hypotension, impotence, increased saliva, tenesmus.

Body as a whole: Frequent: asthenia. Infrequent: edema, falling, fever, malaise,

trauma. Rare: allergic reaction, allergy aggravated, abdominal body sensation,

anaphylactic shock, face edema, hot flashes, increased ESR, pain, restless legs,

rigors, tolerance increased, weight decrease.

Cardiovascular system: Infrequent: cerebrovascular disorder, hypertension,

tachycardia. Rare: angina pectoris, arrhythmia, arteritis, circulatory failure,

extrasystoles, hypertension aggravated, myocardial infarction, phlebitis,

pulmonary embolism, pulmonary edema, varicose veins, ventricular tachycardia.

Central and peripheral nervous system: Frequent: ataxia, confusion, euphoria,

insomnia, vertigo. Infrequent: agitation, decreased cognition, detached,

difficulty concentrating, dysarthria, emotional lability, hallucination,

hypoesthesia, illusion, leg cramps, migraine, paresthesia, sleeping (after

daytime dosing), speech disorder, stupor, tremor. Rare: abnormal gait, abnormal

thinking, aggressive reaction, apathy, appetite increased, decreased libido,

delusion, dementia, depersonalization, dysphasia, feeling strange, hypokinesia,

hypotonia, hysteria, intoxicated feeling, manic reaction, neuralgia, neuritis,

neuropathy, neurosis, panic attacks, paresis, personality disorder,

somnambulism, suicide attempts, tetany, yawning.

Gastrointestinal system: Frequent: hiccup. Infrequent: constipation, dysphagia,

flatulence, gastroenteritis. Rare: enteritis, eructation, esophagospasm,

gastritis, hemorrhoids, intestinal obstruction, rectal hemorrhage, tooth caries.

Hematologic and lymphatic system: Rare: anemia, hyperhemoglobinemia, leukopenia,

lymphadenopathy, macrocytic anemia, purpura, thrombosis.

Immunologic system: Rare: abscess, herpes simplex, herpes zoster, otitis

externa, otitis media.

Liver and biliary system: Infrequent: abnormal hepatic function, increased SGPT.

Rare: bilirubinemia, increased SGOT.

Metabolic and nutritional: Infrequent: hyperglycemia, thirst. Rare: gout,

hypercholesteremia, hyperlipidemia, increased alkaline phosphatase, increased

BUN, periorbital edema.

Musculoskeletal system: Infrequent: arthritis. Rare: arthrosis, muscle weakness,

sciatica, tendinitis.

Reproductive system: Infrequent: menstrual disorder, vaginitis. Rare: breast

fibroadenosis, breast neoplasm, breast pain.

Respiratory system: Infrequent: bronchitis, coughing, dyspnea. Rare:

bronchospasm, epistaxis, hypoxia, laryngitis, pneumonia.

Skin and appendages: Infrequent: pruritus. Rare: acne, bullous eruption,

dermatitis, furunculosis, injection-site inflammation, photosensitivity

reaction, urticaria.

Special senses: Frequent: diplopia, vision abnormal. Infrequent: eye irritation,

eye pain, scleritis, taste perversion, tinnitus. Rare: conjunctivitis, corneal

ulceration, lacrimation abnormal, parosmia, photopsia.

Urogenital system: Infrequent: cystitis, urinary incontinence. Rare: acute renal

failure, dysuria, micturition frequency, nocturia, polyuria, pyelonephritis,

renal pain, urinary retention.

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DRUG ABUSE AND DEPENDENCE

Controlled substance: Zolpidem tartrate is classified as a Schedule IV

controlled substance by federal regulation.

Abuse and dependence: Studies of abuse potential in former drug abusers found

that the effects of single doses of Ambien (zolpidem tartrate) 40 mg were

similar, but not identical, to diazepam 20 mg, while zolpidem tartrate 10 mg was

difficult to distinguish from placebo.

Sedative/hypnotics have produced withdrawal signs and symptoms following abrupt

discontinuation. These reported symptoms range from mild dysphoria and insomnia

to a withdrawal syndrome that may include abdominal and muscle cramps, vomiting,

sweating, tremors, and convulsions. The U.S. clinical trial experience from

zolpidem does not reveal any clear evidence for withdrawal syndrome.

Nevertheless, the following adverse events included in DSM-III-R criteria for

uncomplicated sedative/hypnotic withdrawal were reported during U.S. clinical

trials following placebo substitution occurring within 48 hours following last

zolpidem treatment: fatigue, nausea, flushing, lightheadedness, uncontrolled

crying, emesis, stomach cramps, panic attack, nervousness, and abdominal

discomfort. These reported adverse events occurred at an incidence of 1% or

less. However, available data cannot provide a reliable estimate of the

incidence, if any, of dependence during treatment at recommended doses. Rare

post-marketing reports of abuse, dependence and withdrawal have been received.

Because persons with a history of addiction to, or abuse of, drugs or alcohol

are at increased risk of habituation and dependence, they should be under

careful surveillance when receiving zolpidem or any other hypnotic.

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OVERDOSAGE

Signs and symptoms: In European postmarketing reports of overdose with zolpidem

alone, impairment of consciousness has ranged from somnolence to light coma.

There was one case each of cardiovascular and respiratory compromise.

Individuals have fully recovered from zolpidem tartrate overdoses up to 400 mg

(40 times the maximum recommended dose). Overdose cases involving multiple

CNS-depressant agents, including zolpidem, have resulted in more severe

symptomatology, including fatal outcomes.

Recommended treatment: General symptomatic and supportive measures should be

used along with immediate gastric lavage where appropriate. Intravenous fluids

should be administered as needed. Flumazenil may be useful. As in all cases of

drug overdose, respiration, pulse, blood pressure, and other appropriate signs

should be monitored and general supportive measures employed. Hypotension and

CNS depression should be monitored and treated by appropriate medical

intervention. Sedating drugs should be withheld following zolpidem overdosage,

even if excitation occurs. The value of dialysis in the treatment of overdosage

has not been determined, although hemodialysis studies in patients with renal

failure receiving therapeutic doses have demonstrated that zolpidem is not

dialyzable.

Poison control center: As with the management of all overdosage, the possibility

of multiple drug ingestion should be considered. The physician may wish to

consider contacting a poison control center for up-to-date information on the

management of hypnotic drug product overdosage.

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DOSAGE AND ADMINISTRATION

The dose of Ambien should be individualized.

The recommended dose for adults is 10 mg immediately before bedtime.

Downward dosage adjustment may be necessary when Ambien is administered with

agents having known CNS-depressant effects because of the potentially additive

effects.

Elderly or debilitated patients may be especially sensitive to the effects of

Ambien (zolpidem tartrate). Patients with hepatic insufficiency do not clear the

drug as rapidly as normals. An initial 5-mg dose is recommended in these

patients (see Precautions).

The total Ambien dose should not exceed 10 mg.

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HOW SUPPLIED

Ambien 5-mg tablets are capsule-shaped, pink, film coated, with AMB 5 debossed

on one side and 5401 on the other and supplied as:

NDC Number Size

0024-5401-31 bottle of 100

0024-5401-34 carton of 100 unit dose

0024-5401-50 bottle of 500

Ambien 10-mg tablets are capsule-shaped, white, film coated, with AMB 10

debossed on one side and 5421 on the other and supplied as:

NDC Number Size

0024-5421-31 bottle of 100

0024-5421-34 carton of 100 unit dose

0024-5421-50 bottle of 500

Store at controlled room temperature 20°-25°C (68°-77°F).

Rx only

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INFORMATION FOR PATIENTS TAKING AMBIEN

Your doctor has prescribed Ambien to help you sleep. The following information

is intended to guide you in the safe use of this medicine. It is not meant to

take the place of your doctor's instructions. If you have any questions about

Ambien tablets be sure to ask your doctor or pharmacist.

Ambien is used to treat different types of sleep problems, such as:

.. trouble falling asleep

.. waking up too early in the morning

.. waking up often during the night

Some people may have more than one of these problems.

Ambien belongs to a group of medicines known as the " sedative/hypnotics, " or

simply, sleep medicines. There are many different sleep medicines available to

help people sleep better. Sleep problems are usually temporary, requiring

treatment for only a short time, usually 1 or 2 days up to 1 or 2 weeks. Some

people have chronic sleep problems that may require more prolonged use of sleep

medicine. However, you should not use these medicines for long periods without

talking with your doctor about the risks and benefits of prolonged use.

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SIDE EFFECTS

Most common side effects: All medicines have side effects. Most common side

effects of sleep medicines include:

.. drowsiness

.. dizziness

.. lightheadedness

.. difficulty with coordination

You may find that these medicines make you sleepy during the day. How drowsy you

feel depends upon how your body reacts to the medicine, which sleep medicine you

are taking, and how large a dose your doctor has prescribed. Daytime drowsiness

is best avoided by taking the lowest dose possible that will still help you

sleep at night. Your doctor will work with you to find the dose of Ambien that

is best for you.

To manage these side effects while you are taking this medicine:

.. When you first start taking Ambien or any other sleep med-icine until you know

whether the medicine will still have some carryover effect in you the next day,

use extreme care while doing anything that requires complete alertness, such as

driving a car, operating machinery, or piloting an aircraft.

.. NEVER drink alcohol while you are being treated with Ambien or any sleep

medicine. Alcohol can increase the side effects of Ambien or any other sleep

medicine.

.. Do not take any other medicines without asking your doctor first. This

includes medicines you can buy without a pre-scription. Some medicines can cause

drowsiness and are best avoided while taking Ambien.

.. Always take the exact dose of Ambien prescribed by your doctor. Never change

your dose without talking to your doctor first.

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SPECIAL CONCERNS

There are some special problems that may occur while taking sleep medicines.

Memory problems: Sleep medicines may cause a special type of memory loss or

" amnesia. " When this occurs, a person may not remember what has happened for

several hours after taking the medicine. This is usually not a problem since

most people fall asleep after taking the medicine.

Memory loss can be a problem, however, when sleep medicines are taken while

traveling, such as during an airplane flight and the person wakes up before the

effect of the medicine is gone. This has been called " traveler's amnesia. "

Memory problems are not common while taking Ambien. In most instances memory

problems can be avoided if you take Ambien only when you are able to get a full

night's sleep (7 to 8 hours) before you need to be active again. Be sure to talk

to your doctor if you think you are having memory problems.

Tolerance: When sleep medicines are used every night for more than a few weeks,

they may lose their effectiveness to help you sleep. This is known as

" tolerance.'' Sleep medicines should, in most cases, be used only for short

periods of time, such as 1 or 2 days and generally no longer than 1 or 2 weeks.

If your sleep problems continue, consult your doctor, who will determine whether

other measures are needed to overcome your sleep problems.

Dependence: Sleep medicines can cause dependence, especially when these

medicines are used regularly for longer than a few weeks or at high doses. Some

people develop a need to continue taking their medicines. This is known as

dependence or " addiction. "

When people develop dependence, they may have difficulty stopping the sleep

medicine. If the medicine is suddenly stopped, the body is not able to function

normally and unpleasant symptoms (see Withdrawal) may occur. They may find they

have to keep taking the medicine either at the prescribed dose or at increasing

doses just to avoid withdrawal symptoms.

All people taking sleep medicines have some risk of becoming dependent on the

medicine. However, people who have been dependent on alcohol or other drugs in

the past may have a higher chance of becoming addicted to sleep medicines. This

possibility must be considered before using these medicines for more than a few

weeks.

If you have been addicted to alcohol or drugs in the past, it is important to

tell your doctor before starting Ambien or any sleep medicine.

Withdrawal: Withdrawal symptoms may occur when sleep medicines are stopped

suddenly after being used daily for a long time. In some cases, these symptoms

can occur even if the medicine has been used for only a week or two.

In mild cases, withdrawal symptoms may include unpleasant feelings. In more

severe cases, abdominal and muscle cramps, vomiting, sweating, shakiness, and

rarely, seizures may occur. These more severe withdrawal symptoms are very

uncommon.

Another problem that may occur when sleep medicines are stopped is known as

" rebound insomnia. " This means that a person may have more trouble sleeping the

first few nights after the medicine is stopped than before starting the

medicine. If you should experience rebound insomnia, do not get discouraged.

This problem usually goes away on its own after 1 or 2 nights.

If you have been taking Ambien or any other sleep medicine for more than 1 or 2

weeks, do not stop taking it on your own. Always follow your doctor's

directions.

Changes in behavior and thinking: Some people using sleep medicines have

experienced unusual changes in their thinking and/or behavior. These effects are

not common. However, they have included:

.. more outgoing or aggressive behavior than normal

.. loss of personal identity

.. confusion

.. strange behavior

.. agitation

.. hallucinations

.. worsening of depression

.. suicidal thoughts

How often these effects occur depends on several factors, such as a person's

general health, the use of other medicines, and which sleep medicine is being

used. Clinical experience with Ambien suggests that it is uncommonly associated

with these behavior changes.

It is also important to realize that it is rarely clear whether these behavior

changes are caused by the medicine, an illness, or occur on their own. In fact,

sleep problems that do not improve may be due to illnesses that were present

before the medicine was used. If you or your family notice any changes in your

behavior, or if you have any unusual or disturbing thoughts, call your doctor

immediately.

Pregnancy: Sleep medicines may cause sedation of the unborn baby when used

during the last weeks of pregnancy.

Be sure to tell your doctor if you are pregnant, if you are planning to become

pregnant, or if you become pregnant while taking Ambien.

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SAFE USE OF SLEEPING MEDICINES

To ensure the safe and effective use of Ambien or any other sleep medicine, you

should observe the following cautions:

1. Ambien is a prescription medicine and should be used ONLY as directed by your

doctor. Follow your doctor's instructions about how to take, when to take, and

how long to take Ambien.

2. Never use Ambien or any other sleep medicine for longer than directed by your

doctor.

3. If you notice any unusual and/or disturbing thoughts or behavior during

treatment with Ambien or any other sleep medicine, contact your doctor.

4. Tell your doctor about any medicines you may be taking, including medicines

you may buy without a prescription. You should also tell your doctor if you

drink alcohol. DO NOT use alcohol while taking Ambien or any other sleep

medicine.

5. Do not take Ambien unless you are able to get a full night's sleep before you

must be active again. For example, Ambien should not be taken on an overnight

airplane flight of less than 7 to 8 hours since " traveler's amnesia " may occur.

6. Do not increase the prescribed dose of Ambien or any other sleep medicine

unless instructed by your doctor.

7. When you first start taking Ambien or any other sleep medicine until you know

whether the medicine will still have some carryover effect in you the next day,

use extreme care while doing anything that requires complete alertness, such as

driving a car, operating machinery, or piloting an aircraft.

8. Be aware that you may have more sleeping problems the first night or two

after stopping Ambien or any other sleep medicine.

9. Be sure to tell your doctor if you are pregnant, if you are planning to

become pregnant, or if you become pregnant while taking Ambien.

10. As with all prescription medicines, never share Ambien or any other sleep

medicine with anyone else. Always store Ambien or any other sleep medicine in

the original container out of reach of children.

11. Ambien works very quickly. You should only take Ambien right before going to

bed and are ready to go to sleep.

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Distributed by:

Sanofi-Synthelabo Inc.

New York, NY 10016

ZSS-5A Revised August 2002